Cellular transplantation is an attractive and growing treatment strategy for a variety of diverse disease processes including diabetes, Parkinson's, myocardial ischemia, single-gene liver defects, hemophilia and hypoparathyroidism. Transplantation of human cancer cells into mice may help to direct therapies using personalized medicine approaches. The availability of genetically engineered stem cells now provides many possibilities for therapeutic cellular replacement in regenerative medicine.
Intrahepatic transplantation of isolated insulin-secreting pancreatic islets of Langerhans is a prototypic example of a highly successful cellular replacement therapy in patients with type 1 diabetes mellitus (T1DM) with unstable glucose control. The “Edmonton Protocol” became a milestone by reporting high rates of insulin independence after islet transplant in patients with difficult-to-control diabetes1. Long-term analysis of these initial results indicated that insulin independence was not durable. Most patients returned to moderate amounts of insulin approximately five years post-transplant, while maintaining the absence of recurrent hypoglycemia2.
The intrahepatic vascular space provides nutritional and physical support for islets after islets are stripped of their vascularized and specialized extracellular matrix3,4. Transplanting islets within the liver has been associated with procedural risks of bleeding and thrombosis, and localized steatosis. Additional factors leading to gradual graft attrition suggest that the liver may not be the optimal site for cellular transplantation of insulin-secreting cells5,6. The death of significant numbers of intraportal islets in the immediate post-transplant period from tissue-factor triggered platelet injury (the instant blood mediated inflammatory reaction), compounded by ischemia from immature revascularization contribute to impaired islet survival and function long-term7. To regain proper islet function, new blood vessels need to form around and within the graft; however, these newly formed vessels result in a vascular density that is chronically lower than that within the native islets8, 9. This is irrespective of whether the islets are transplanted into the kidney, spleen, or infused intraportally9. The vascular density is not influenced by hyperglycemia or engraftment time, but numerous vessels form in the surrounding connective tissue8.
As new, alternative stem cell derived insulin-secreting cells become available, easily retrievable sites become an imperative priority as the safety profile of potentially teratogenic cell lines are defined in patients. As a consequence, intensified research effort has been dedicated to the pursuit of alternative transplant sites9-11.
It has been suggested that an optimal cellular transplantation site should: 1) have an adequate tissue volume capacity, 2) be in close proximity to vascular networks, ensuring sufficient oxygen supply prior to revascularization, 3) allow for dynamic communication between the cellular graft and systemic circulation in a physiologically relevant manner, 4) facilitate a minimally invasive means to transplant, biopsy and retrieve if required, and 5) elicit minimal inflammation to reduce immunogenicity and promote long-term survival11.
The subcutaneous site is an attractive surrogate for portal vein islet infusion, due to the minimally invasive and simplistic characteristics of transplanting into this space, as well as the potential to monitor the cellular transplant through novel imaging techniques12-14. However, transplantation of islets into an unmodified subcutaneous site has universally failed to reverse diabetes in animal models and in human studies, due to poor oxygen tension and hypovascularity15. Stimulation of angiogenesis is a critical determinant of successful subcutaneous cell transplant therapy9, 11, 14, 16. The use of oxygen generators, macro-device polymers, meshes, encapsulation technologies, matrices and growth factors including fibroblast growth factor, hepatocyte growth factor, vascular endothelial growth factor and co-transplantation of mesenchymal stem cells have been explored with some success. Inopportunely, the foreign body and inflammatory reaction at the interface between the host tissue and implanted biomaterial persists for the in vivo lifetime of the implant17. Ultimately, this response forms a thick avascular collagenous fibrotic capsule, which physically separates the biomaterial from the host. This in turn hinders metabolic exchange, cell signaling, healing, tissue-device integration, and the formation of microenvironments for opportunistic bacterial infections and ultimately engraftment failure17, 18.
Few alternative islet engraftment strategies have translated into the clinical setting, and the inventor is not aware of any that have rendered patients completely independent of insulin. There remains a need in the art for methods of cellular transplantation which may improve upon the prior art.